Optimizing commercial trials

Because of a concern that continuous application of organic acids is causing microbial resistance, research is needed on alternative application protocols and to expand the diversity of potential antimicrobials with practical application to food production. To successfully achieve this, it is essential to explore the interaction between the food matrix and food-borne pathogens (Ricke et al., 2005). 

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Bartholic et al. (1991) have already reported on a commercial trial with a short contact FCC device (called Msec — millisecond catalytic cracking). The relative change in yields they observed compared to conventional FCC is reported in Table 9. Those yields are encouraging, but represent only the first step as the hardware and the catalyst are far from optimized. 

The purification of value-added pharmaceuticals in the past required multiple chromatographic steps for batch purification processes. The design and optimization of these processes were often cumbersome and the operations were fundamentally complex. Individual batch processes requires optimization between chromatographic efficiency and enantioselectivity, which results in major economic ramifications. An additional problem was the extremely short time for development of the purification process. Commercial constraints demand that the time interval between non-optimized laboratory bench purification and the first process-scale production for clinical trials are kept to a minimum. Therefore, rapid process design and optimization methods based on computer aided simulation of an SMB process will assist at this stage. 

Trial objectives may also incorporate commercial imperatives. The marketing department may suggest that the treatment regimen must be once per day to be successful in the market. This requirement affects optimal dose... 

Both pre-clinical and clinical trials are underpinned by a necessity to produce sufficient quantities of the prospective drug for its evaluation. Depending on the biopharmaceutical product, this could require from several hundred grams to over a kilo of active ingredient. Typical production protocols for biopharmaceutical products are outlined in detail in Chapter 3. It is important that a suitable production process be designed prior to commencement of pre-clinical trials, that the process be amenable to scale-up and, as far as is practicable, that it is optimized (Figure 2.9). The material used for pre-clinical and clinical trials should be produced using the same process by which it is intended to undertake final commercial-scale manufacture. 

In the quarter of a century since Kohler and Milstein s ground-breaking work, more than 100,000 MABs have been reported. Many researchers were quick to recognize the therapeutic potential of MABs and from the late 1970s academic and commercial laboratories rushed to produce MABs specific for a range of human diseases. This initial optimism was soon suppressed as clinical trials began to show that mouse... 

Following successful phase II clinical trials, the manufacture of the dmg substance is scaled up to meet commercialization needs. In addition, the prototype formulation and process is optimized and scaled up to greater than one-tenth of the commercial batch size. 

Advances in stem cell therapy have received a great deal of press in recent years. Unfortunately, when public expectations have been raised, patients are likely to search for non-orthodox sources of treatment. There are tens of thousands of internet pages extolling the promise of stem cells, and various forms of stem cell therapy are available on a commercial basis in a number of countries, including China, South America, and Eastern Europe. However, most administer the stem cells in an uncontrolled way and do not have long term follow-up so that rational scientific conclusions cannot be reached. The science provides hope for potential therapeutic interventions in neurodegenerative diseases, but it is in its early stages and much is still needed to be learned about how to control stem cell proliferation, differentiation into specific cells and optimal functional recovery in animal models before human trials. The collection and use of human fetal tissue may also raise ethical concerns. 

Process development activities to optimize rSLPI production for clinical trials were subject to time constraints. Subsequent to this production campaign, we are continuing to optimize the process for rSLPI, since it will be a commercially important product. It must, however, be recognized that process changes will be reviewed for their impact on the quality and efficacy of the final product. 

Larger volume product supplies are typically for late-stage clinical trials and then commercial manufacture. These will be in the order of hundreds of kg to multi-tons. At this stage further optimization will be conducted. Typically the catalytic step will be more rigorously defined to obtain the most efficient use of the... 

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